The multifunctional nature of transforming growth factor-b (TGF-b) underlies its involvement in many pathologies, including neurodegenerative diseases. Changes that may occur in the expression of protein and mRNA for TGF-b isoforms in response to various disease states and tissue treatments are being investigated using immunohistochemistry and RT-PCR techniques. There is increased expression of TGF-b2 in astrocytes in brains from patients with familial and sporadic Alzheimer's disease (AD) when compared to controls. There is also expression of TGF-b2 in neurons exhibiting neurofibrillary tangles. This increased expression is also found in eight other neurodegenerative diseases. We are now investigating changes in TGF-b receptor expression in AD. In primary cultures of rat embryo hippocampal neurons and in hNT cells (a terminally differentiated human cell line) TGF-bs can protect against the damaging effects of treatment with b- amyloid peptide b-AP. TGF-b treatment before addition of b-AP causes a two-to three-fold increase in cell survival. These protective effects are accompanied by increased expression of "anti-apoptotic" genes such as Bcl-Xs and decreased expression of "pro-apoptotic" genes such as Bax and Bcl-XL. Additionally, we are investigating the ability of TGF-b to alter expression of wild-type and mutant presenilins, the recently cloned genes that regulate processing and production of b-AP.